We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase–positive NSCLC.
Patients were randomized 1:1 to take either oral ...brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS.
Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4–12.8) versus 16.7 months (11.6–21.4). Median OS was 29.5 months (18.2–not reached) versus 34.1 months (27.7–not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%–25%, 26%–50%, 51%–75%, and 76%–100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up.
Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials.
Climatic changes, including altered precipitation regimes, will affect key ecosystem processes, such as plant productivity and biodiversity for many terrestrial ecosystems. Past and ongoing ...precipitation experiments have been conducted to quantify these potential changes. An analysis of these experiments indicates that they have provided important information on how water regulates ecosystem processes. However, they do not adequately represent global biomes nor forecasted precipitation scenarios and their potential contribution to advance our understanding of ecosystem responses to precipitation changes is therefore limited, as is their potential value for the development and testing of ecosystem models. This highlights the need for new precipitation experiments in biomes and ambient climatic conditions hitherto poorly studied applying relevant complex scenarios including changes in precipitation frequency and amplitude, seasonality, extremity and interactions with other global change drivers. A systematic and holistic approach to investigate how soil and plant community characteristics change with altered precipitation regimes and the consequent effects on ecosystem processes and functioning within these experiments will greatly increase their value to the climate change and ecosystem research communities. Experiments should specifically test how changes in precipitation leading to exceedance of biological thresholds affect ecosystem resilience and acclimation.
In the 2022 mpox-outbreak most patients presented with mild symptoms. Central nervous system (CNS) involvement has previously been described as a rare and severe complication of mpox; however, ...diagnostic findings in cerebrospinal fluid (CSF) analysis and neuroimaging studies have only been reported in one case previously.
We report a previously healthy 37-year-old man with mpox complicated by encephalitis. He first presented with painful skin lesions and genital ulcers; polymerase chain reaction (PCR) from the lesions was positive for mpox. Twelve days later he was admitted with fever and confusion. Neuroimaging and CSF analysis indicated encephalitis. The CSF was PCR-negative for monkeypox virus but intrathecal antibody production was detected. He spontaneously improved over a few days course and recovered fully.
This case of mpox-associated encephalitis shows that CNS involvement in mpox infection may have a relatively mild clinical course, and that detection of intrathecal antibody production can be used to establish the diagnosis if CSF monkeypox virus-PCR is negative.
The response of forest ecosystems to increased atmospheric CO₂is constrained by nutrient availability. It is thus crucial to account for nutrient limitation when studying the forest response to ...climate change. The objectives of this study were to describe the nutritional status of the main European tree species, to identify growth‐limiting nutrients and to assess changes in tree nutrition during the past two decades. We analysed the foliar nutrition data collected during 1992–2009 on the intensive forest monitoring plots of the ICP Forests programme. Of the 22 significant temporal trends that were observed in foliar nutrient concentrations, 20 were decreasing and two were increasing. Some of these trends were alarming, among which the foliar P concentration in F. sylvatica, Q. Petraea and P. sylvestris that significantly deteriorated during 1992–2009. In Q. Petraea and P. sylvestris, the decrease in foliar P concentration was more pronounced on plots with low foliar P status, meaning that trees with latent P deficiency could become deficient in the near future. Increased tree productivity, possibly resulting from high N deposition and from the global increase in atmospheric CO₂, has led to higher nutrient demand by trees. As the soil nutrient supply was not always sufficient to meet the demands of faster growing trees, this could partly explain the deterioration of tree mineral nutrition. The results suggest that when evaluating forest carbon storage capacity and when planning to reduce CO₂emissions by increasing use of wood biomass for bioenergy, it is crucial that nutrient limitations for forest growth are considered.
C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an ...autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP-1 was shown to cleave high m.w. kininogen into bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with different paraclinical and clinical outcomes of HAE. We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100 controls. Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE patients compared with matched controls (p < 0.0001). The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with the level of C1-INH (p = 0.0009 and p = 0.0047, respectively), the level of C4 (p = 0.0084 and p < 0.0001, respectively), and the number of attacks in the year of blood sampling (p = 0.0075 and p = 0.0058, respectively). In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood. The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients compared with controls. Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of complement C4 consumption, as well as the severity of disease. These results suggest that MASP-1 may exert a previously unrecognized role in the pathophysiology of HAE.
Background: To investigate effect and toxicity of immune checkpoint inhibition (ICI) in a Danish real-life non-small cell lung cancer (NSCLC) population. By including patients underrepresented in ...clinical trials, such as those with brain metastasis (BM), higher age, more comorbidity and poorer performance status (ECOG), comparison of unselected patients to clinical trial populations is possible.
Material and methods: Real life data were gathered from 118 consecutive NSCLC patients with incurable NSCLC treated with ICI at the Department of Oncology at the University Hospital of Odense, Denmark from September 2015 to April 2018. Immune-related adverse events (irAEs) grades 3-5 were registered prospectively during the same period. Additional patient related data were obtained retrospectively from patients' files. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier estimates, the log-rank test and cox regression analysis performed for factors affecting survival.
Results: Median age for patients was 66 years (IQR 59-71) and 62 years (range: 55-64) for those with BM. Females 63%; adenocarcinoma (AC)/squamous/others 69%/23%/8%; ECOG ≥ 2 10%; bone/brain/liver metastases 36%/18%/15%; PD-L1 (TPS) <1%/ ≥ 1%/ ≤ 49%/ ≥ 50%/NR: 3%/14%/68%/15%; baseline autoimmunity 10%, Charlson's Comorbidity Index Score (CCIS) ≥ 2 39%, treatment line: 1st/2nd/ ≥ 3rd 39%/30%/31%. Median OS for patients receiving ICI in ≥2 line was 11.5 months versus not reached in first line (HR 2.6, 95% CI: 1.3-5.0, p = .005). For patients with BM, the median OS was 8.2 months (HR 1.38, 95% CI: 0.7-2.5, p = .37). Twenty-four percent of patients terminated ICI due to irAE grades 3-5 alone (grade 5, n = 1), which were not associated with higher age or BM.
Conclusions: OS and PFS were comparable to clinical trial reports. Long-lasting remission is also possible in patients with BM. Real-life populations have higher rates of irAE grades 3 and 4 than reported in clinical trials, but it does not seem to impact median OS.
•Stand density and age were strong predictors of European forest growth.•We found direct and indirect impacts of N deposition on forest growth.•Forest growth showed a positive, but in some cases ...quadratic response to N deposition.•Beech forest growth was significantly reduced at high N deposition levels.•Climate predictors were species-specifically related to European forest growth.•There was limited evidence of an ozone impact on European forest growth.
Changing environmental conditions may substantially interact with site quality and forest stand characteristics, and impact forest growth and carbon sequestration. Understanding the impact of the various drivers of forest growth is therefore critical to predict how forest ecosystems can respond to climate change. We conducted a continental-scale analysis of recent (1995–2010) forest volume increment data (ΔVol, m3 ha−1 yr−1), obtained from ca. 100,000 coniferous and broadleaved trees in 442 even-aged, single-species stands across 23 European countries. We used multivariate statistical approaches, such as mixed effects models and structural equation modelling to investigate how European forest growth respond to changes in 11 predictors, including stand characteristics, climate conditions, air and site quality, as well as their interactions. We found that, despite the large environmental gradients encompassed by the forests examined, stand density and age were key drivers of forest growth. We further detected a positive, in some cases non-linear effect of N deposition, most pronounced for beech forests, with a tipping point at ca. 30 kg N ha−1 yr−1. With the exception of a consistent temperature signal on Norway spruce, climate-related predictors and ground-level ozone showed much less generalized relationships with ΔVol. Our results show that, together with the driving forces exerted by stand density and age, N deposition is at least as important as climate to modulate forest growth at continental scale in Europe, with a potential negative effect at sites with high N deposition.
Acid deposition arising from sulphur (S) and nitrogen (N) emissions from fossil fuel combustion and agriculture has contributed to the acidification of terrestrial ecosystems in many regions ...globally. However, in Europe and North America, S deposition has greatly decreased in recent decades due to emissions controls. In this study, we assessed the response of soil solution chemistry in mineral horizons of European forests to these changes. Trends in pH, acid neutralizing capacity (ANC), major ions, total aluminium (Altot) and dissolved organic carbon were determined for the period 1995–2012. Plots with at least 10 years of observations from the ICP Forests monitoring network were used. Trends were assessed for the upper mineral soil (10–20 cm, 104 plots) and subsoil (40–80 cm, 162 plots). There was a large decrease in the concentration of sulphate (SO42−) in soil solution; over a 10‐year period (2000–2010), SO42− decreased by 52% at 10–20 cm and 40% at 40–80 cm. Nitrate was unchanged at 10–20 cm but decreased at 40–80 cm. The decrease in acid anions was accompanied by a large and significant decrease in the concentration of the nutrient base cations: calcium, magnesium and potassium (Bc = Ca2+ + Mg2+ + K+) and Altot over the entire dataset. The response of soil solution acidity was nonuniform. At 10–20 cm, ANC increased in acid‐sensitive soils (base saturation ≤10%) indicating a recovery, but ANC decreased in soils with base saturation >10%. At 40–80 cm, ANC remained unchanged in acid‐sensitive soils (base saturation ≤20%, pHCaCl2 ≤ 4.5) and decreased in better‐buffered soils (base saturation >20%, pHCaCl2 > 4.5). In addition, the molar ratio of Bc to Altot either did not change or decreased. The results suggest a long‐time lag between emission abatement and changes in soil solution acidity and underline the importance of long‐term monitoring in evaluating ecosystem response to decreases in deposition.
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•EGFR mutations were present in ctDNA at PD to first line TKI in 70 % of cases.•T790 M in ctDNA was consistently completely cleared on osimertinib treatment.•Sensitizing EGFR ...mutations were cleared in 62 % of cases.•Non-clearers had significantly shorter PFS and lower ORR and DCR than clearers.•Initial monitoring of ctDNA predicted outcome to osimertinib.
Tyrosine kinase inhibitors (TKIs) are first line treatment choices for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). However, responses vary among patients, therefore good biomarkers predicting better responses are required. EGFR mutations are detected in the blood from patients as circulating tumour DNA (ctDNA). Studies have shown that clearing ctDNA during first line TKI treatment predicts outcomes for first and second generation TKI treatments. We aimed to investigate the effects on outcome measures of ctDNA clearing in subsequent treatment lines to treatment with the third generation TKI osimertinib.
In total, 225 patients were included in a prospective, multicentre study, where consecutive blood samples were monitored for EGFR mutations during systemic treatment lines, using the Cobas® EGFR mutation test v2. This study focused on EGFR mutations in ctDNA of 82 systemically pre-treated patients receiving osimertinib.
Clearing all EGFR mutations from the blood after osimertinib treatment, significantly predicted progression-free survival, objective response rates and disease control rates. Primary sensitising EGFR mutations were found in ctDNA in 70 % of patients, and were accompanied by the T790 M mutation in nearly two thirds of cases. The T790 M mutation was cleared in all cases, while the accompanying sensitising mutations did not necessarily clear. However, T790 M clearing without simultaneously clearing of the primary sensitising mutation did not predict clinical responses. Neither the detection of T790 M before osimertinib treatment, nor the presence of EGFR mutations at the time of osimertinib initiation predicted clinical outcomes.
The clearing of EGFR mutations in ctDNA after osimertinib treatment initiation in patients with advanced NSCLC is useful as a positive predictor of clinical outcome.
• Nitrogen (N) availability is known to influence ectomycorrhizal fungal components, such as fungal community composition, biomass of root tips and production of mycelia, but effects have never been ...demonstrated within the same forest. • We measured concurrently the abundance of ectomycorrhizal root tips and the production of external mycelia, and explored the changes in the ectomycorrhizal community composition, across a stand‐scale N deposition gradient (from 27 to 43 kg N ha−1 yr−1) at the edge of a spruce forest. The N status was affected along the gradient as shown by a range of N availability indices. • Ectomycorrhizal root tip abundance and mycelial production decreased five and 10‐fold, respectively, with increasing N deposition. In addition, the ectomycorrhizal fungal community changed and the species richness decreased. The changes were correlated with the measured indices of N status, in particular N deposition and N leaching. • The relationship between the altered ectomycorrhizal community, root tip abundance and mycelial production is discussed in the context of the N parameters. We suggest that increased N deposition to forests will cause large changes in ectomycorrhizal fungal community structure and functioning, which, in turn, may result in reduced N uptake by roots and fungi, and increased losses of N by leaching.
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